chr19-6495053-C-G

Variant names:

• chr19-6495053-C-G
• rs446199
• NM_006087.4:c.*111G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006087.4(TUBB4A):​c.*111G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 1,308,468 control chromosomes in the GnomAD database, including 372,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44103 hom., cov: 27)
  • Exomes 𝑓: 0.75 (328652 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.50
• Publications: 7 publications found

Genes affected

TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]

TUBB4A Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• TUBB4A-related neurologic disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• torsion dystonia 4

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000268191 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-6495053-C-G is Benign according to our data. Variant chr19-6495053-C-G is described in ClinVar as Benign. ClinVar VariationId is 330256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	NM_006087.4	MANE Select	c.*111G>C		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*111G>C		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*111G>C		3_prime_UTR	Exon 5 of 5	NP_001276056.1	M0R278

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.*111G>C		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*985G>C		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	TUBB4A	ENST00000598635.2	TSL:4	c.*111G>C		downstream_gene	N/A	ENSP00000470627.2	M0QZL7

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115154 AN: 151090 Hom.: 44070 Cov.: 27

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.767

GnomAD4 exome AF: 0.753 AC: 871148 AN: 1157258 Hom.: 328652 Cov.: 16 AF XY: 0.751 AC XY: 431983 AN XY: 575204

African (AFR) AF: 0.752 AC: 20138 AN: 26762

American (AMR) AF: 0.854 AC: 26125 AN: 30590

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 14590 AN: 19832

East Asian (EAS) AF: 0.752 AC: 26706 AN: 35512

South Asian (SAS) AF: 0.715 AC: 48375 AN: 67624

European-Finnish (FIN) AF: 0.810 AC: 38659 AN: 47722

Middle Eastern (MID) AF: 0.713 AC: 2497 AN: 3500

European-Non Finnish (NFE) AF: 0.750 AC: 656979 AN: 876164

Other (OTH) AF: 0.748 AC: 37079 AN: 49552

GnomAD4 genome AF: 0.762 AC: 115244 AN: 151210 Hom.: 44103 Cov.: 27 AF XY: 0.763 AC XY: 56367 AN XY: 73832

African (AFR) AF: 0.757 AC: 31181 AN: 41174

American (AMR) AF: 0.810 AC: 12271 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 2523 AN: 3466

East Asian (EAS) AF: 0.712 AC: 3615 AN: 5074

South Asian (SAS) AF: 0.722 AC: 3449 AN: 4774

European-Finnish (FIN) AF: 0.838 AC: 8792 AN: 10486

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51090 AN: 67786

Other (OTH) AF: 0.770 AC: 1614 AN: 2096

Alfa AF: 0.685 Hom.: 1574

Bravo AF: 0.759

Asia WGS AF: 0.745 AC: 2593 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hypomyelinating leukodystrophy 6 (1)
-	-	1	Torsion dystonia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.26
DANN	Benign	0.45
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs446199; hg19: chr19-6495064;